Nothing Special   »   [go: up one dir, main page]

EP3329917B1 - Therapeutic and/or prophylactic agent for adult t cell leukemia/lymphoma - Google Patents

Therapeutic and/or prophylactic agent for adult t cell leukemia/lymphoma Download PDF

Info

Publication number
EP3329917B1
EP3329917B1 EP16830602.5A EP16830602A EP3329917B1 EP 3329917 B1 EP3329917 B1 EP 3329917B1 EP 16830602 A EP16830602 A EP 16830602A EP 3329917 B1 EP3329917 B1 EP 3329917B1
Authority
EP
European Patent Office
Prior art keywords
dimethyl
adult
trans
cell leukemia
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP16830602.5A
Other languages
German (de)
French (fr)
Other versions
EP3329917A4 (en
EP3329917A1 (en
Inventor
Toshiki Watanabe
Makoto Yamagishi
Osamu Kanno
Jun Watanabe
Nobuaki ADACHI
Daisuke Honma
Yoshito HAMADA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Daiichi Sankyo Co Ltd
University of Tokyo NUC
Original Assignee
Daiichi Sankyo Co Ltd
University of Tokyo NUC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daiichi Sankyo Co Ltd, University of Tokyo NUC filed Critical Daiichi Sankyo Co Ltd
Publication of EP3329917A1 publication Critical patent/EP3329917A1/en
Publication of EP3329917A4 publication Critical patent/EP3329917A4/en
Application granted granted Critical
Publication of EP3329917B1 publication Critical patent/EP3329917B1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to an agent for treating and/or preventing adult T cell leukemia/lymphoma containing a compound having a specific chemical structure or a pharmaceutically acceptable salt thereof.
  • HTLV-1 infected peripheral blood T cells In adult T cell leukemia/lymphoma (ATL), a plurality of genetic abnormalities are accumulated in HTLV-1 infected peripheral blood T cells during a long latent period of 50 to 60 years, which can cause malignant transformation. It is presumed that there are 20 million or more human adult T-cell leukemia virus type I (HTLV-1) infected persons (carriers) in the world, and it is presumed that there are 1.08 million or more infected persons, and ATL develops in about 1200 persons every year in Japan (Non Patent Literature 1).
  • HTLV-1 human adult T-cell leukemia virus type I
  • Non Patent Literature 2 It has been revealed, as a result of cohort study, that ATL develops only in carriers in which a ratio of HTLV-1 infected cells in peripheral blood (provirus load, PVL) is 4% or more (Non Patent Literature 2). This group of persons with high risk of development occupies 25% in the entire carriers, and it is expected that reduction of the number of infected cells would lead to reduction of risk of the ATL development. There are, however, a large number of unclear points in molecular mechanisms of immortalization and tumorigenesis of cells caused by HTLV-1 and of refractoriness, and there has been found neither an effective method for treating ATL nor a method for selectively removing infected cells.
  • Non Patent Literature 3 Owing to appearance of an anti-CCR4 antibody, that is, a molecular target drug against ATL, the treatment outcome has been improved, but the prognosis is still the worst among those of malignant lymphomas (Non Patent Literature 3), and in terms of median survival, the treatment outcome of chemotherapy for acute ATL is 12.7 months (Non Patent Literature 4) and the treatment outcome by the CCR4 antibody against recurrence is 13.7 months (Non Patent Literature 5). Accordingly, it is imperative, based on medical condition elucidation at the molecular level, to prevent the virus infection, to prevent the leukemia development and to develop a novel treatment method.
  • ATL cells are a population having a very uniform and abnormal gene expression pattern (Non Patent Literature 6).
  • ATL cells have characteristic signal transduction system abnormality, which corresponds to a key of survival and growth of tumor cells, and it has been revealed that the abnormality is derived from accumulation of epigenetic abnormalities (Non Patent Literature 7).
  • Enhancer of Zeste Homologue 1/2 corresponds to active center of Polycomb Repressive Complex 2 (PRC2) that trimethylates histone H3K27.
  • PRC2 Polycomb Repressive Complex 2
  • EZH1 and EZH2 retain an epigenome in a cell while mutually compensating their functions. Inhibition of EZH2 leads to reduction of methylation level of H3K27 throughout the cell, but this effect is restricted by the compensating effect of EZH1.
  • EZH1 and EZH2 are simultaneously inhibited, the methylation can be more effectively eliminated (Non Patent Literature 8).
  • Non Patent Literatures 9 and 10 It has been found that abnormality in a PRC2 component leads to cancer or abnormality in stem cell function, and in particular, accumulation of methylated H3K27me3 induced by gene abnormality or increased expression of EZH2 is identified in a large number of cancers, and earnest studies are being conducted mainly for EZH2 as a novel cancer molecular target drug (Non Patent Literatures 9 and 10).
  • Non Patent Literatures 6 and 11 The abnormality of polycomb family occurring in ATL was cleared by exhaustive gene expression analysis (Non Patent Literatures 6 and 11).
  • overexpression of EZH2 is conspicuous, and increase of the methylation level of H3K27 in the entire cells is also detected.
  • EZH2-dependent inhibition of miR-31 results in expression of NF- ⁇ B Inducing Kinase (NIK) so as to constitutively activate NF- ⁇ B pathway, and hence, EZH2 is regarded as effective as a molecular target drug against ATL.
  • NIK NF- ⁇ B Inducing Kinase
  • the present invention provides an agent for treating and/or preventing adult T cell leukemia/lymphoma containing a compound having a specific chemical structure or a pharmaceutically acceptable salt thereof.
  • the present invention was accomplished on the basis of this finding.
  • ATL adult T cell leukemia/lymphoma
  • HTLV-1 human T cell leukemia virus type 1
  • ATL is sometimes designated also as “adult T cell leukemia” or “adult T cell lymphoma”.
  • HTLV-1 carrier means a subject (a warm-blooded animal, particularly a human) infected with HTLV-1 virus. If a subject has an antibody to HTLV-1, the subject can be regarded as an HTLV-1 carrier.
  • the term "prevent” and derivatives thereof mean that the onset rate of ATL in an HTLV-1 carrier before the onset of ATL is reduced.
  • the term means that the onset of ATL is prevented in preferably 60% or more, and more preferably 80% or more of subjects belonging to an HTLV-1 carrier group.
  • treat and derivatives thereof mean remission, relief, and/or delay of worsening of ATL clinical symptoms in a patient that has developed ATL.
  • a physician can diagnose ATL based on clinical symptoms of a subject.
  • ATL is a disease caused by monoclonal growth of T cells in which HTLV-1 has been incorporated into the genome as a provirus, and hence ATL can be diagnosed by detecting, by a Southern blot method or the like, that HTLV-1 provirus is monoclonally incorporated into a DNA of ATL cells contained in a sample obtained from a subject.
  • a test method for diagnosing that a subject is an HTLV-1 carrier As a test method for diagnosing that a subject is an HTLV-1 carrier, a particle agglutination assay (PA assay), a chemiluminescence assay, an indirect fluorescent antibody assay using a virus-infected cell as an antigen, and a Western blot method are known, and any of these can be appropriately employed.
  • PA assay particle agglutination assay
  • a chemiluminescence assay chemiluminescence assay
  • an indirect fluorescent antibody assay using a virus-infected cell as an antigen As a test method for diagnosing that a subject is an HTLV-1 carrier, a particle agglutination assay (PA assay), a chemiluminescence assay, an indirect fluorescent antibody assay using a virus-infected cell as an antigen, and a Western blot method are known, and any of these can be appropriately employed.
  • any of the following compounds and pharmaceutically acceptable salts thereof can be used for preventing and/or treating ATL.
  • the compound for the use of the present invention can optionally be in the form of a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt refers to a salt that does not have remarkable toxicity but can be used as a pharmaceutical.
  • the compound for the use of the present invention has a basic group, and hence can be converted into a salt by a reaction with an acid.
  • Examples of the salt for a basic group include inorganic acid salts such as halogenated hydroacid salts including hydrofluoride, hydrochloride, hydrobromide and hydroiodide, nitrate, perchlorate, sulfate and phosphate; organic acid salts such as C 1 -C 6 alkyl sulfonates including methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate, aryl sulfonates including benzene sulfonate and p-toluenesulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, adipate, and maleate; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and aspartate.
  • inorganic acid salts such as halogenated hydroa
  • the pharmaceutically acceptable salt of the compound for the use of the present invention may be converted to a hydrate by incorporation of a water molecule in some cases if the salt is left in the air or is reprecipitated, and such a hydrate is embraced in the salt for the use of the present invention.
  • the pharmaceutically acceptable salt of the compound for the use of the present invention may be converted to a solvate by absorption of some sort of solvent in some cases if the salt is left in the solvent or is reprecipitated, and such a solvate is embraced in the salt for the use of the present invention.
  • the present invention also embraces a compound converted, through a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, into a compound of Example 1 or a compound of Example 2 corresponding to an active ingredient of a pharmaceutical composition for the use of the present invention, namely, a compound converted into the compound of Example 1 or the compound of Example 2 by enzymatic oxidation, reduction, hydrolysis or the like, or a "pharmaceutically acceptable prodrug compound" converted into the compound of Example 1 or the compound of Example 2 by hydrolysis or the like caused by gastric acid or the like.
  • the compound for the use of the present invention or the pharmaceutically acceptable salt thereof can be isolated and purified by any of known methods, such as extraction, precipitation, distillation, chromatography, separation by precipitation, and reprecipitation.
  • the compound for the use of the present invention can contain, in one or more atoms constituting the compound, an isotope in a non-natural ratio.
  • the isotope include heavy hydrogen ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) and carbon-14 ( 14 C).
  • the compound can be radiolabeled with a radioactive isotope such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • the radiolabeled compound is useful as a therapeutic or prophylactic agent, a research reagent such as an assay reagent, and a diagnostic agent such as an in-vivo image diagnostic agent. It is noted that all isotopic variants of the compound for the use of the present invention are embraced in the scope of the present invention no matter whether they are radioactive or not.
  • the compound for the use of the present invention or the pharmaceutically acceptable salt thereof may be used together with another antitumor agent.
  • the antitumor agent include an alkylating agent, an antimetabolite, an antitumor antibiotic, an antineoplastic plant extract, a BRM (biological response modifier), a hormone, a vitamin, an antitumor antibody, a molecular targeted drug, and other antitumor agents.
  • alkylating agent examples include alkylating agent such as nitrogen mustard, nitrogen mustard N-oxide or chlorambucil, an aziridine-based alkylating agent such as carboquone or thiotepa, an epoxide-based alkylating agent such as di-bromo-mannitol or di-bromo-dulcitol, a nitrosourea-based alkylating agent such as carmustine, lomustine, semustine, nimustine hydrochloride, streptozocin, chlorozotocin, or ranimustine, and busulfan, improsulfan tosilate, and dacarbazine.
  • alkylating agent such as nitrogen mustard, nitrogen mustard N-oxide or chlorambucil
  • an aziridine-based alkylating agent such as carboquone or thiotepa
  • an epoxide-based alkylating agent such as di-bromo-mannitol or di-bro
  • antimetabolites examples include a purine antimetabolite such as 6-mercaptopurine, 6-thioguanine or thioinosine, a pyrimidine antimetabolite such as fluorouracil, tegafur, tegafur-uracil, carmofur, doxifluridine, broxuridine, cytarabine, or enocitabine, and a folic acid metabolite such as methotrexate or trimetrexate.
  • a purine antimetabolite such as 6-mercaptopurine, 6-thioguanine or thioinosine
  • a pyrimidine antimetabolite such as fluorouracil, tegafur, tegafur-uracil, carmofur, doxifluridine, broxuridine, cytarabine, or enocitabine
  • a folic acid metabolite such as methotrexate or trimetrexate.
  • antitumor antibiotic examples include an anthracycline-based antibiotic antitumor agent such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarbicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin, or epirubicin, and chromomycin A3 and actinomycin D.
  • anthracycline-based antibiotic antitumor agent such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarbicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin, or epirubicin, and chromomycin A3 and actinomycin D.
  • antineoplastic plant extract examples include vinca alkaloids such as vindesine, vincristine and vinblastine, taxanes such as paclitaxel and docetaxel, and epipodophyllotoxins such as etoposide and teniposide.
  • Examples of the BRM include a tumor necrosis factor and indomethacin.
  • hormones examples include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, prasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, methenolone, fosfestrol, ethinylestradiol, chlormadinone and medroxyprogesterone.
  • vitamin C examples include vitamin C and vitamin A.
  • antitumor antibody and the molecular targeted drug examples include trastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab, infliximab, imatinib mesylate, gefitinib, erlotinib, sunitinib, lapatinib, and sorafenib.
  • antitumor agents examples include cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, aceglatone, schizophyllan, picibanil, procarbazine, pipobroman, neocarzinostatin, hydroxyurea, ubenimex, and krestin.
  • the compound for the use of the present invention or the pharmaceutically acceptable salt thereof can be administered in various forms.
  • the dosage forms include oral administration in the form of a tablet, a capsule, a granule, an emulsion, a pill, a powder, and a syrup (a solution), and parenteral administration in the form of an injection (intravenous, intramuscular, subcutaneous or intraperitoneal administration), a drip infusion, and a suppository (rectal administration).
  • compositions can be formulated by an ordinary method using a principal agent together with an auxiliary agent usually used in the field of pharmaceutical formulation, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension, and a coating agent.
  • an auxiliary agent usually used in the field of pharmaceutical formulation, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension, and a coating agent.
  • a carrier to be used can be, for example, an excipient such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, or silicic acid; a binder such as water, ethanol, propanol, simple syrup, a glucose solution, a starch solution, a gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, or polyvinyl pyrrolidone; a disintegrating agent such as dry starch, sodium alginate, an agar powder, a laminaran powder, sodium hydrogen carbonate, calcium carbonate, a polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, monoglyceride stearate, starch, or lactose; a disintegration inhibitor such as white sugar, stearin, cacao butter, or a hydrogenated oil; an absorption promoter such as lactose, white sugar, sodium chloride,
  • the tablet can be provided with a usual coating if necessary, and can be in the form of, for example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, or a film-coated tablet, or a bilayer tablet or a multilayer tablet.
  • a carrier to be used can be an excipient such as glucose, lactose, cacao butter, starch, a hydrogenated vegetable oil, kaolin, or talc; a binder such as a gum arabic powder, powdered tragacanth, gelatin, or ethanol; or a disintegrating agent such as laminaran, or agar.
  • any of carriers known in this technical field can be widely used, and examples include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.
  • the compound or the salt can be used as a solution, an emulsion or a suspension.
  • the solution, the emulsion or the suspension is preferably sterilized, and isotonic to blood.
  • a solvent used for preparing the solution, the emulsion or the suspension is not especially limited as long as the solvent can be used as a diluent for medical use, and examples include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and a polyoxyethylene sorbitan fatty acid ester.
  • the preparation may contain common salt, glucose or glycerin in an amount sufficient for preparing an isotonic solution, and may contain a usual solubilizing agent, buffer, soothing agent or the like.
  • the above-described formulation can contain, if necessary, a colorant, a preservative, a perfume, a flavoring agent, a sweetener or the like, and may further contain another pharmaceutical.
  • An amount of the compound contained as the active ingredient in the formulation is not especially limited but is appropriately selected from a wide range, and is usually 0.5 to 70% by weight, and preferably 1 to 30% by weight in the entire composition.
  • the amount of use is varied depending on the symptom, the age and the like of a patient (a warm-blooded animal, particularly a human), and in the case of oral administration, it is preferably administered to an adult once through six times per day depending on the symptom, with the upper limit per day set to 2000 mg (preferably 100 mg) and the lower limit set to 0.1 mg (preferably 1 mg, and more preferably 10 mg).
  • the present invention provides the use in a method for treating ATL in a patient suffering from ATL, including administering the compound or the pharmaceutically acceptable salt thereof to the patient.
  • the present invention also provides the use in a method for preventing onset of ATL in a subject of an HTLV-1 carrier, including administering the compound or the pharmaceutically acceptable salt thereof to the subject.
  • the present invention provides a pharmaceutical composition for use in treating ATL in a patient suffering from ATL, containing the compound or the pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition for use in prevention of onset of ATL in a subject of an HTLV-1 carrier, containing the compound or the pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition for the use of the present invention may contain a pharmaceutically acceptable excipient in addition to the compound or the pharmaceutically acceptable salt thereof.
  • the present invention provides the compound or the pharmaceutically acceptable salt thereof for use in treating ATL in a patient suffering from ATL.
  • the present invention also provides the compound or the pharmaceutically acceptable salt thereof for use in prevention of onset of ATL in a subject of an HTLV-1 carrier.
  • the present invention provides use of the compound or the pharmaceutically acceptable salt thereof in production of a pharmaceutical composition for use in treating ATL in a patient suffering from ATL.
  • the present invention also provides use of the compound or the pharmaceutically acceptable salt thereof for use in production of a pharmaceutical composition to be used in prevention of onset of ATL in a subject of an HTLV-1 carrier.
  • the compound for the use of the present invention or the pharmaceutically acceptable salt thereof can reduce growth of adult T cell leukemia/lymphoma, can lower a survival rate of adult T cell leukemia/lymphoma, and/or can kill adult T cell leukemia/lymphoma.
  • the present invention provides a composition or a pharmaceutical composition to be used for reducing growth of adult T cell leukemia/lymphoma, for lowering a survival rate of adult T cell leukemia/lymphoma, and/or for killing adult T cell leukemia/lymphoma, containing the compound or the pharmaceutically acceptable salt thereof.
  • Methyl 3,4-dihydroxy-2-methylbenzoate (43.1 g, 237 mmol) was dissolved in acetic acid (250 mL) and dichloromethane (250 mL), a dichloromethane solution (20 mL) of bromine (37.8 g, 237 mmol) was added thereto in a dropwise manner over 15 minutes while cooling over ice, and the resultant was stirred at the same temperature for 4 hours. Thereafter, bromide (3.78 g, 23.7 mmol) was further added to the resultant, the resulting mixture was stirred for 1.5 hours while cooling over ice, and iced water was added to the resultant reaction solution followed by extraction with ethyl acetate.
  • step 1-1 A reaction similar to that of step 1-1 was performed by using the methyl 5-bromo-3,4-dihydroxy-2-methylbenzoate (23.5 g, 90.0 mmol) synthesized in Reference Example 3, the tert-butyl N-(trans-4-ethynylcyclohexyl)carbamate (22.1 g, 99.0 mmol) synthesized in Reference Example 2, triruthenium dodecacarbonyl (0) (1.44 g, 2.25 mmol) and 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-[1,4']bipyrazole (3.42 g, 6.75 mmol) to obtain a title compound (38.9 g, 80.3 mmol, 89% yield).
  • step 1-3 A reaction similar to that of step 1-3 was performed by using the (2R)-methyl 7-bromo-2-[trans-4-(tert-butoxycarbonylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylate (the second peak, 0.956 g, 1.97 mmol) separated in step 2-2, tetrahydrofuran (6 mL), methanol (3 mL), and a 1M sodium hydroxide aqueous solution (2.96 mL, 2.96 mmol) to obtain a title compound (0.903 g, 1.92 mmol, 97% yield).
  • step 1-4 A reaction similar to that of step 1-4 was performed by using the (2R)-7-bromo-[trans-4-(tert-butoxycarbonylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid (0.903 g, 1.92 mmol) synthesized in step 2-3, dimethylformamide (20 mL), 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one hydrochloride (0.399 g, 2.11 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.442 g, 2.30 mmol), 1-hydroxy-7-azabenzotriazole (0.314 g, 2.30 mmol), and N,N-diisopropylethylamine (0.803 mL, 4.61 mmol) to obtain a title compound (0.801 g, 1.32 m
  • step 1-5 A reaction similar to that of step 1-5 was performed by using the tert-butyl N-[trans-4-[(2R)-7-boromo-5-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl]-2,4-dimethyl-1,3-benzodioxol-2-yl]cyclohexyl]carbamate (0.801, g, 1.32 mmol) synthesized in step 2-4, methanol (1.5 mL), and a 4M hydrochloric acid-1,4-dioxane solution (1.67 mL, 6.62 mmol) to obtain a title compound (0.668 g, 1.32 mmol, 100% yield).
  • step 1-6 A reaction similar to that of step 1-6 was performed by using the (2R)-2-(trans-4-aminocyclohexyl)-7-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide (21.1 g, 41.7 mmol) synthesized in step 2-5, methanol (250 mL), a 37% formaldehyde aqueous solution (7.12 g, 87.8 mmol), and sodium triacetoxyborohydride (38.8 g, 146 mmol) to obtain a title compound (15.1 g, 28.4 mmol, 68% yield).
  • step 1-3 A reaction similar to that of step 1-3 was performed by using the methyl 7-bromo-2-[trans-4-(tert-botoxycarbonylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylate (23.5 g, 48.5 mmol) synthesized in step 2-1, tetrahydrofuran (120 mL), methanol (60 mL), and a 1M sodium hydroxide aqueous solution (72.8 mL, 72.8 mmol) to obtain a title compound (22.8 g, 48.5 mmol, 100% yield).
  • step 1-4 A reaction similar to that of step 1-4 was performed by using the 7-bromo-2-[trans-4-(tert-butoxycarbonylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid (22.8 g, 48.5 mmol) synthesized in step 3-2, dimethylformamide (300 mL), 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one hydrochloride (10.1 g, 53.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.2 g, 58.2 mmol), 1-hydroxy-7-azabenzotriazole (7.92 g, 58.2 mmol), and N,N-diisopropylethylamine (20.3 mL, 146 mmol) to obtain a title compound (26.8 g, 44.3
  • step 1-5 A reaction similar to that of step 1-5 was performed by using the tert-butyl N-[trans-4-[7-bromo-5-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl]-2,4-dimethyl-1,3-benzodioxol-2-yl] cyclohexyl] carbamate (6.04 g, 9.99 mmol) synthesized in step 3-2, methanol (10 mL), and a 4M hydrochloric acid-1,4-dioxane solution (12.5 mL, 50.0 mmol) to obtain a title compound (4.20 g, 8.30 mmol, 83% yield).
  • step 1-6 A reaction similar to that of step 1-6 was performed by using the 2-(trans-4-aminocyclohexyl)-7-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide (21.0 g, 41.6 mmol) synthesized in step 3-3, dichloromethane (500 mL), a 37% formaldehyde aqueous solution (8.45 g, 104 mmol), and sodium triacetoxyborohydride (55.2 g, 208 mmol) to obtain a title compound (20.0 g, 37.6 mmol, 90% yield).
  • a cell line TL-Om1 derived from an ATL patient tumor cell was provided by Dr. Kazuo Sugamura, Chief Executive, Local Incorporated Administrative Agency Miyagi Prefectural Hospital Organization.
  • the cell line TL-Om1 was suspended in a medium (RPMI 1640 medium (Invitrogen) supplemented with 10% fetal bovine serum (FBS, Invitrogen)), and seeded in a 12-well plate at a density of 1 x 10 5 cells/1 mL/well.
  • a dilution series of the compound of Example 1 or Example 3 prepared by using DMSO was added thereto, and the resultant was cultured under conditions of 37°C and 5% CO 2 .
  • the cells were collected every two or three days, and passage-cultured by transferring 300 ⁇ L of the culture medium to a 12-well plate containing 1 mL of a fresh medium. Besides, the dilution series of the compound of Example 1 or Example 3 was added again to continuously carry out the cultivation. On days 3, 5, 7, 10, 12 and 14 after starting the cultivation, the cells were collected from the culture medium to obtain a cell density, and thus, the influence of the compound of Example 1 or Example 3 on the cell growth was examined. The number of cells on each of these days was obtained by WST-8 (Dojindo Laboratories).
  • the cultured cells were seeded in a 96-well plate by 100 ⁇ L, WST-8 was added to each well to a final concentration of 10%, and the resultant plate was incubated at 37°C for 2 hours.
  • An absorbance at 450 nm of each sample was measured by using a plate reader (iMark Microplate Reader, Biorad).
  • a calibration curve between the number of cells and the absorbance was obtained, and the number of cells was calculated on the basis of the absorbance obtained in an actual test.
  • the number of cells was calculated in each passage, and the cell growth rate of each compound-treated group was calculated assuming that the cell growth of a DMSO-treated group was 100%.
  • the results are illustrated in Figures 1 and 2 .
  • PBMCs peripheral blood monocular cells
  • the PBMCs were suspended in a medium (PRMI 1640 medium supplemented with 10% patient plasma), and seeded in a 48-well plate at a density of 3 x 10 5 cells/300 ⁇ L/well (ATL Nos. 1 to 5) or 2 x 10 5 cells/300 ⁇ L/well (ATL Nos. 6 to 26).
  • a medium PRMI 1640 medium supplemented with 10% patient plasma
  • IL-2R IL-2R
  • IL-2 R & C Systems, Inc.
  • the thus cultured cells were seeded in a 96-well plate by 100 ⁇ L, WST-8 was added to each well to a final concentration of 10%, the resulting plate was incubated at 37°C for 4 hours, and an absorbance at 450 nm was measured as an index of the cell density in the medium solution.
  • the results are illustrated in Figure 3 . As a result, it was revealed that the compound can be used for treating ATL.
  • PBMCs containing HTLV-1 infected cells were obtained by centrifugation using Ficoll.
  • the PBMCs were suspended in a medium (RPMI 1640 medium supplemented with 10% FBS), and seeded in a 48-well plate at a density of 5 x 10 5 cells/250 ⁇ L/well. Thereafter, DMSO or the compound of Example 1 or Example 3 in a final concentration of 100 nM was added thereto, and the resultant was cultured under conditions of 37°C and 5% CO 2 for 10 to 12 days.
  • the cultured cells were collected, and genomic DNA was extracted therefrom by using QIAmp DNA Blood Mini Kit (QIAGEN).
  • a primer and a probe for the RNase P genes were purchased from Applied Biosystems, Inc.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

    Technical Field
  • The present invention relates to an agent for treating and/or preventing adult T cell leukemia/lymphoma containing a compound having a specific chemical structure or a pharmaceutically acceptable salt thereof.
    • Background Art
  • In adult T cell leukemia/lymphoma (ATL), a plurality of genetic abnormalities are accumulated in HTLV-1 infected peripheral blood T cells during a long latent period of 50 to 60 years, which can cause malignant transformation. It is presumed that there are 20 million or more human adult T-cell leukemia virus type I (HTLV-1) infected persons (carriers) in the world, and it is presumed that there are 1.08 million or more infected persons, and ATL develops in about 1200 persons every year in Japan (Non Patent Literature 1). It has been revealed, as a result of cohort study, that ATL develops only in carriers in which a ratio of HTLV-1 infected cells in peripheral blood (provirus load, PVL) is 4% or more (Non Patent Literature 2). This group of persons with high risk of development occupies 25% in the entire carriers, and it is expected that reduction of the number of infected cells would lead to reduction of risk of the ATL development. There are, however, a large number of unclear points in molecular mechanisms of immortalization and tumorigenesis of cells caused by HTLV-1 and of refractoriness, and there has been found neither an effective method for treating ATL nor a method for selectively removing infected cells. Owing to appearance of an anti-CCR4 antibody, that is, a molecular target drug against ATL, the treatment outcome has been improved, but the prognosis is still the worst among those of malignant lymphomas (Non Patent Literature 3), and in terms of median survival, the treatment outcome of chemotherapy for acute ATL is 12.7 months (Non Patent Literature 4) and the treatment outcome by the CCR4 antibody against recurrence is 13.7 months (Non Patent Literature 5). Accordingly, it is imperative, based on medical condition elucidation at the molecular level, to prevent the virus infection, to prevent the leukemia development and to develop a novel treatment method.
  • It has been revealed, as a result of large scale analysis of gene expression using a large number of ATL clinical samples, that ATL cells are a population having a very uniform and abnormal gene expression pattern (Non Patent Literature 6). Besides, ATL cells have characteristic signal transduction system abnormality, which corresponds to a key of survival and growth of tumor cells, and it has been revealed that the abnormality is derived from accumulation of epigenetic abnormalities (Non Patent Literature 7).
  • The polycomb family negatively controls gene expression through chromatin control by histone modification. Enhancer of Zeste Homologue 1/2 (EZH1/2) corresponds to active center of Polycomb Repressive Complex 2 (PRC2) that trimethylates histone H3K27. EZH1 and EZH2 retain an epigenome in a cell while mutually compensating their functions. Inhibition of EZH2 leads to reduction of methylation level of H3K27 throughout the cell, but this effect is restricted by the compensating effect of EZH1. When EZH1 and EZH2 are simultaneously inhibited, the methylation can be more effectively eliminated (Non Patent Literature 8). It has been found that abnormality in a PRC2 component leads to cancer or abnormality in stem cell function, and in particular, accumulation of methylated H3K27me3 induced by gene abnormality or increased expression of EZH2 is identified in a large number of cancers, and earnest studies are being conducted mainly for EZH2 as a novel cancer molecular target drug (Non Patent Literatures 9 and 10).
  • The abnormality of polycomb family occurring in ATL was cleared by exhaustive gene expression analysis (Non Patent Literatures 6 and 11). In particular, overexpression of EZH2 is conspicuous, and increase of the methylation level of H3K27 in the entire cells is also detected. Besides, it has been cleared that EZH2-dependent inhibition of miR-31 results in expression of NF-κB Inducing Kinase (NIK) so as to constitutively activate NF-κB pathway, and hence, EZH2 is regarded as effective as a molecular target drug against ATL.
    • Citation List Non Patent Literature
    • Non Patent Literature 1: Yamaguchi K., Watanabe T., Int J Hematol 2002; 76 Suppl 2: 240
    • Non Patent Literature 2: Iwanaga, M. et al., Blood 2010; 116(8): 1211-9
    • Non Patent Literature 3: Vose, Armitage, J. et al., J Clin Oncol 2008; 26(25): 4124-30
    • Non Patent Literature 4: Utsunomiya A. et al., J Clin Oncol 2007; 25(34): 5458-64
    • Non Patent Literature 5: Ishida, Joh, et al., J Clin Oncol 2012; 30(8): 837-42
    • Non Patent Literature 6: Yamagishi M. et al., Cancer Cell 2012; 21: 121
    • Non Patent Literature 7: Yamagishi M., Watanabe T., Front Microbiol 2012; 3: 334
    • Non Patent Literature 8: Shen, X. et al., Mol Cell 2008; 32 (4) : 491-502
    • Non Patent Literature 9: Sparmann A., van Lohuizen M., Nat Rev Cancer 2006; 6: 846
    • Non Patent Literature 10: Lund, Adams, Copland., Leukemia 2014; 28(1): 44-9
    • Non Patent Literature 11: Sasaki D. et al., Haematologica 2011; 96: 712
    Summary of Invention Technical Problem
  • The present invention provides an agent for treating and/or preventing adult T cell leukemia/lymphoma containing a compound having a specific chemical structure or a pharmaceutically acceptable salt thereof.
    • Solution to Problem
  • The present inventors have cleared that (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, or (2R)-7-bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof is remarkably effective for treating and preventing adult T cell leukemia/lymphoma. The present invention was accomplished on the basis of this finding.
  • According to the present invention, inventions according to the following [1] to [8] are provided.
    1. [1] 7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, or 7-bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, for use in treating adult T cell leukemia/lymphoma in a patient suffering from adult T cell leukemia/lymphoma.
    2. [2] (2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, for use in treating adult T cell leukemia/lymphoma in a patient suffering from adult T cell leukemia/lymphoma.
    3. [3] (2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide p-toluenesulfonate, for use in treating adult T cell leukemia/lymphoma in a patient suffering from adult T cell leukemia/lymphoma.
    4. [4] (2R)-7-Bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, for use in treating adult T cell leukemia/lymphoma in a patient suffering from adult T cell leukemia/lymphoma.
    5. [5] 7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, or 7-bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, for use in preventing onset of adult T cell leukemia/lymphoma in a subject of a human adult T cell leukemia virus type I (HTLV-1) carrier.
    6. [6] (2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, for use in preventing onset of adult T cell leukemia/lymphoma in a subject of a human adult T cell leukemia virus type I (HTLV-1) carrier.
    7. [7] (2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide p-toluenesulfonate, for use in preventing onset of adult T cell leukemia/lymphoma in a subject of a human adult T cell leukemia virus type I (HTLV-1) carrier.
    8. [8] (2R)-7-Bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, for use in preventing onset of adult T cell leukemia/lymphoma in a subject of a human adult T cell leukemia virus type I (HTLV-1) carrier.
    Brief Description of Drawings
    • [Figure 1] Figures 1A and 1B illustrate growth of cell line TL-Om1 derived from ATL patient tumor cells having been treated with a compound of Example 1 over time (Figure 1A) and dose-dependently (Figure 1B). The growth is plotted such that cell growth of a DMSO-treated group is 100%.
    • [Figure 2] Figures 2A and 2B illustrate growth of cell line TL-Om1 derived from ATL patient tumor cells having been treated with a compound of Example 3 over time (Figure 2A) and dose-dependently (Figure 2B). The growth is plotted such that cell growth of a DMSO-treated group is 100%.
    • [Figure 3] Figure 3 illustrates an effect of the compound for the use of the present invention on growth of peripheral blood mononuclear cells isolated from ATL patients (26 cases).
    • [Figure 4] Figure 4 illustrates an effect of the compound for the use of the present invention on a ratio of infected cells (PVL) in peripheral blood mononuclear cells isolated from HTLV-1 carrier samples.
    Description of Embodiment
  • Herein, the term "adult T cell leukemia/lymphoma" (hereinafter, sometimes simply referred to "ATL") refers to leukemia/lymphoma caused by infection with human T cell leukemia virus type 1 (HTLV-1). ATL is sometimes designated also as "adult T cell leukemia" or "adult T cell lymphoma".
  • Herein, the term "HTLV-1 carrier" means a subject (a warm-blooded animal, particularly a human) infected with HTLV-1 virus. If a subject has an antibody to HTLV-1, the subject can be regarded as an HTLV-1 carrier.
  • Herein, the term "prevent" and derivatives thereof mean that the onset rate of ATL in an HTLV-1 carrier before the onset of ATL is reduced. The term means that the onset of ATL is prevented in preferably 60% or more, and more preferably 80% or more of subjects belonging to an HTLV-1 carrier group.
  • Herein, the term "treat" and derivatives thereof mean remission, relief, and/or delay of worsening of ATL clinical symptoms in a patient that has developed ATL.
  • A physician can diagnose ATL based on clinical symptoms of a subject. Besides, ATL is a disease caused by monoclonal growth of T cells in which HTLV-1 has been incorporated into the genome as a provirus, and hence ATL can be diagnosed by detecting, by a Southern blot method or the like, that HTLV-1 provirus is monoclonally incorporated into a DNA of ATL cells contained in a sample obtained from a subject.
  • As a test method for diagnosing that a subject is an HTLV-1 carrier, a particle agglutination assay (PA assay), a chemiluminescence assay, an indirect fluorescent antibody assay using a virus-infected cell as an antigen, and a Western blot method are known, and any of these can be appropriately employed. In the Western blot method, if an antibody to virus envelope protein (gp46) is positive and one or more antibodies to three core proteins (p19, p24 and p53) are positive in a sample obtained from a subject, it can be diagnosed that the subject is an HTLV-1 carrier. Alternatively, it can be subsidiarily diagnosed, by a polymerase chain reaction (PCR) for amplifying HTLV-1 provirus genome, whether or not the subject is a carrier.
  • According to the present invention, any of the following compounds and pharmaceutically acceptable salts thereof can be used for preventing and/or treating ATL.
    • (2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide, or a pharmaceutically acceptable salt thereof:
  • Figure imgb0001
    Figure imgb0002
    • (2R)-7-Bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide, or a pharmaceutically acceptable salt thereof:
  • Figure imgb0003
  • The compound for the use of the present invention can optionally be in the form of a pharmaceutically acceptable salt. A pharmaceutically acceptable salt refers to a salt that does not have remarkable toxicity but can be used as a pharmaceutical. The compound for the use of the present invention has a basic group, and hence can be converted into a salt by a reaction with an acid.
  • Examples of the salt for a basic group include inorganic acid salts such as halogenated hydroacid salts including hydrofluoride, hydrochloride, hydrobromide and hydroiodide, nitrate, perchlorate, sulfate and phosphate; organic acid salts such as C1-C6 alkyl sulfonates including methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate, aryl sulfonates including benzene sulfonate and p-toluenesulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, adipate, and maleate; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and aspartate.
  • The pharmaceutically acceptable salt of the compound for the use of the present invention may be converted to a hydrate by incorporation of a water molecule in some cases if the salt is left in the air or is reprecipitated, and such a hydrate is embraced in the salt for the use of the present invention.
  • The pharmaceutically acceptable salt of the compound for the use of the present invention may be converted to a solvate by absorption of some sort of solvent in some cases if the salt is left in the solvent or is reprecipitated, and such a solvate is embraced in the salt for the use of the present invention.
  • Besides, the present invention also embraces a compound converted, through a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, into a compound of Example 1 or a compound of Example 2 corresponding to an active ingredient of a pharmaceutical composition for the use of the present invention, namely, a compound converted into the compound of Example 1 or the compound of Example 2 by enzymatic oxidation, reduction, hydrolysis or the like, or a "pharmaceutically acceptable prodrug compound" converted into the compound of Example 1 or the compound of Example 2 by hydrolysis or the like caused by gastric acid or the like.
  • The compound for the use of the present invention or the pharmaceutically acceptable salt thereof can be isolated and purified by any of known methods, such as extraction, precipitation, distillation, chromatography, separation by precipitation, and reprecipitation.
  • The compound for the use of the present invention can contain, in one or more atoms constituting the compound, an isotope in a non-natural ratio. Examples of the isotope include heavy hydrogen (2H), tritium (3H), iodine-125 (125I) and carbon-14 (14C). Besides, the compound can be radiolabeled with a radioactive isotope such as tritium (3H), iodine-125 (125I) or carbon-14 (14C). The radiolabeled compound is useful as a therapeutic or prophylactic agent, a research reagent such as an assay reagent, and a diagnostic agent such as an in-vivo image diagnostic agent. It is noted that all isotopic variants of the compound for the use of the present invention are embraced in the scope of the present invention no matter whether they are radioactive or not.
  • The compound for the use of the present invention or the pharmaceutically acceptable salt thereof may be used together with another antitumor agent. Examples of the antitumor agent include an alkylating agent, an antimetabolite, an antitumor antibiotic, an antineoplastic plant extract, a BRM (biological response modifier), a hormone, a vitamin, an antitumor antibody, a molecular targeted drug, and other antitumor agents.
  • More specifically, examples of the alkylating agent include alkylating agent such as nitrogen mustard, nitrogen mustard N-oxide or chlorambucil, an aziridine-based alkylating agent such as carboquone or thiotepa, an epoxide-based alkylating agent such as di-bromo-mannitol or di-bromo-dulcitol, a nitrosourea-based alkylating agent such as carmustine, lomustine, semustine, nimustine hydrochloride, streptozocin, chlorozotocin, or ranimustine, and busulfan, improsulfan tosilate, and dacarbazine.
  • Examples of various antimetabolites include a purine antimetabolite such as 6-mercaptopurine, 6-thioguanine or thioinosine, a pyrimidine antimetabolite such as fluorouracil, tegafur, tegafur-uracil, carmofur, doxifluridine, broxuridine, cytarabine, or enocitabine, and a folic acid metabolite such as methotrexate or trimetrexate.
  • Examples of the antitumor antibiotic include an anthracycline-based antibiotic antitumor agent such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarbicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin, or epirubicin, and chromomycin A3 and actinomycin D.
  • Examples of the antineoplastic plant extract include vinca alkaloids such as vindesine, vincristine and vinblastine, taxanes such as paclitaxel and docetaxel, and epipodophyllotoxins such as etoposide and teniposide.
  • Examples of the BRM include a tumor necrosis factor and indomethacin.
  • Examples of the hormone include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, prasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, methenolone, fosfestrol, ethinylestradiol, chlormadinone and medroxyprogesterone.
  • Examples of the vitamin include vitamin C and vitamin A.
  • Examples of the antitumor antibody and the molecular targeted drug include trastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab, infliximab, imatinib mesylate, gefitinib, erlotinib, sunitinib, lapatinib, and sorafenib.
  • Examples of the other antitumor agents include cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, aceglatone, schizophyllan, picibanil, procarbazine, pipobroman, neocarzinostatin, hydroxyurea, ubenimex, and krestin.
  • The compound for the use of the present invention or the pharmaceutically acceptable salt thereof can be administered in various forms. Examples of the dosage forms include oral administration in the form of a tablet, a capsule, a granule, an emulsion, a pill, a powder, and a syrup (a solution), and parenteral administration in the form of an injection (intravenous, intramuscular, subcutaneous or intraperitoneal administration), a drip infusion, and a suppository (rectal administration). These various preparations can be formulated by an ordinary method using a principal agent together with an auxiliary agent usually used in the field of pharmaceutical formulation, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension, and a coating agent.
  • When the compound or the salt is used in the form of a tablet, a carrier to be used can be, for example, an excipient such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, or silicic acid; a binder such as water, ethanol, propanol, simple syrup, a glucose solution, a starch solution, a gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, or polyvinyl pyrrolidone; a disintegrating agent such as dry starch, sodium alginate, an agar powder, a laminaran powder, sodium hydrogen carbonate, calcium carbonate, a polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, monoglyceride stearate, starch, or lactose; a disintegration inhibitor such as white sugar, stearin, cacao butter, or a hydrogenated oil; an absorption promoter such as a quaternary ammonium salt, or sodium lauryl sulfate; a moisturizing agent such as glycerin or starch; an adsorbent such as starch, lactose, kaolin, bentonite, or colloidal silicic acid; or a lubricant such as purified talc, stearate salt, a boric acid powder, or polyethylene glycol. Besides, the tablet can be provided with a usual coating if necessary, and can be in the form of, for example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, or a film-coated tablet, or a bilayer tablet or a multilayer tablet.
  • When the compound or the salt is used in the form of a pill, a carrier to be used can be an excipient such as glucose, lactose, cacao butter, starch, a hydrogenated vegetable oil, kaolin, or talc; a binder such as a gum arabic powder, powdered tragacanth, gelatin, or ethanol; or a disintegrating agent such as laminaran, or agar.
  • When the compound or the salt is used in the form of a suppository, any of carriers known in this technical field can be widely used, and examples include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.
  • When used in the form of an injection, the compound or the salt can be used as a solution, an emulsion or a suspension. The solution, the emulsion or the suspension is preferably sterilized, and isotonic to blood. A solvent used for preparing the solution, the emulsion or the suspension is not especially limited as long as the solvent can be used as a diluent for medical use, and examples include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and a polyoxyethylene sorbitan fatty acid ester. In this case, the preparation may contain common salt, glucose or glycerin in an amount sufficient for preparing an isotonic solution, and may contain a usual solubilizing agent, buffer, soothing agent or the like.
  • Besides, the above-described formulation can contain, if necessary, a colorant, a preservative, a perfume, a flavoring agent, a sweetener or the like, and may further contain another pharmaceutical.
  • An amount of the compound contained as the active ingredient in the formulation is not especially limited but is appropriately selected from a wide range, and is usually 0.5 to 70% by weight, and preferably 1 to 30% by weight in the entire composition.
  • The amount of use is varied depending on the symptom, the age and the like of a patient (a warm-blooded animal, particularly a human), and in the case of oral administration, it is preferably administered to an adult once through six times per day depending on the symptom, with the upper limit per day set to 2000 mg (preferably 100 mg) and the lower limit set to 0.1 mg (preferably 1 mg, and more preferably 10 mg).
  • The present invention provides the use in a method for treating ATL in a patient suffering from ATL, including administering the compound or the pharmaceutically acceptable salt thereof to the patient. The present invention also provides the use in a method for preventing onset of ATL in a subject of an HTLV-1 carrier, including administering the compound or the pharmaceutically acceptable salt thereof to the subject.
  • The present invention provides a pharmaceutical composition for use in treating ATL in a patient suffering from ATL, containing the compound or the pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition for use in prevention of onset of ATL in a subject of an HTLV-1 carrier, containing the compound or the pharmaceutically acceptable salt thereof.
  • The pharmaceutical composition for the use of the present invention may contain a pharmaceutically acceptable excipient in addition to the compound or the pharmaceutically acceptable salt thereof.
  • The present invention provides the compound or the pharmaceutically acceptable salt thereof for use in treating ATL in a patient suffering from ATL. The present invention also provides the compound or the pharmaceutically acceptable salt thereof for use in prevention of onset of ATL in a subject of an HTLV-1 carrier. The present invention provides use of the compound or the pharmaceutically acceptable salt thereof in production of a pharmaceutical composition for use in treating ATL in a patient suffering from ATL. The present invention also provides use of the compound or the pharmaceutically acceptable salt thereof for use in production of a pharmaceutical composition to be used in prevention of onset of ATL in a subject of an HTLV-1 carrier.
  • According to Text Examples 1 to 3 described below, the compound for the use of the present invention or the pharmaceutically acceptable salt thereof can reduce growth of adult T cell leukemia/lymphoma, can lower a survival rate of adult T cell leukemia/lymphoma, and/or can kill adult T cell leukemia/lymphoma. Accordingly, the present invention provides a composition or a pharmaceutical composition to be used for reducing growth of adult T cell leukemia/lymphoma, for lowering a survival rate of adult T cell leukemia/lymphoma, and/or for killing adult T cell leukemia/lymphoma, containing the compound or the pharmaceutically acceptable salt thereof.
    • Examples Reference Example 1 Methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate
  • Figure imgb0004
  • Methyl 3,4-dihydroxy-2-methylbenzoate (12.1 g, 66.2 mmol) was dissolved in ethyl acetate (265 mL), N-chlorosuccinimide (13.3 g, 99.2 mmol) was added thereto, the resultant was stirred at room temperature for 1 hour, and p-anisole (7.15 g, 66.2 mmol) was added to the resultant, followed by stirring another 15 minutes. The thus obtained reaction solution was washed with water and a saturated saline solution, and the resultant was dried over magnesium sulfate and concentrated under reduced pressure. The thus obtained residue was washed with dichloromethane to obtain a title compound (8.03 g, 37.1 mmol, 56% yield).
    1H-NMR (400MHz, DMSO-d6) δ: 2.34 (3H, s), 3.76 (3H, s), 7.36 (1H, s), 9.11 (1H, br s), 9.96 (1H, br s). MS (ESI) m/z: 215 (M-H)-.
    • Reference Example 2 tert-Butyl N-(trans-4-ethynylcyclohexyl)carbamate
  • Figure imgb0005
  • To a methanol solution (30 mL) of tert-butyl N-(trans-4-formylcyclohexyl)carbamate (0.856 g, 3.77 mmol), potassium carbonate (1.04 g, 7.54 mmol) and 1-diazo-1-dimethoxyphophoryl-propan-2-one (0.565 mL, 3.77 mmol) were added, and the resultant was stirred at room temperature for 16 hours. To the thus obtained reaction solution, water was added, the resultant was extracted with ethyl acetate, the resulting organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 100:0 to 85:15) to obtain a title compound (0.678 g, 3.04 mmol, 81% yield).
    1H-NMR (400MHz, CDCl3) δ: 1.04-1.17 (2H, m), 1.42-1.55 (2H, m), 1.44 (9H, s), 1.94-2.05 (4H, m), 2.04 (1H, d, J = 2.5 Hz), 2.16-2.25 (1H, m), 3.34-3.50 (1H, m), 4.29-4.43 (1H, br s).
    • Reference Example 3 Methyl 5-bromo-3,4-dihydroxy-2-methylbenzoate
  • Figure imgb0006
  • Methyl 3,4-dihydroxy-2-methylbenzoate (43.1 g, 237 mmol) was dissolved in acetic acid (250 mL) and dichloromethane (250 mL), a dichloromethane solution (20 mL) of bromine (37.8 g, 237 mmol) was added thereto in a dropwise manner over 15 minutes while cooling over ice, and the resultant was stirred at the same temperature for 4 hours. Thereafter, bromide (3.78 g, 23.7 mmol) was further added to the resultant, the resulting mixture was stirred for 1.5 hours while cooling over ice, and iced water was added to the resultant reaction solution followed by extraction with ethyl acetate. The resulting organic layer was washed with a sodium sulfite aqueous solution and a saturated saline solution, and was concentrated under reduced pressure. The thus obtained residue was washed with dichloromethane to obtain a title compound (50.4 g, 193 mmol, 82% yield).
    1H-NMR (400MHz, CDCl3) δ: 2.47 (3H, s), 3.87 (3H, s), 5.61 (1H, br s), 5.83 (1H, br s), 7.67 (1H, s). MS (ESI) m/z: 259, 261 (M-H)-.
    • Example 1 (2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide
  • Figure imgb0007
    • (Step 1-1) Methyl 2-[trans-4-(tert-butoxycarbonylamino)cyclohexyl]-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate
  • To a toluene solution (50 mL) of the methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate (1.00 g, 4.62 mmol) synthesized in Reference Example 1 and the tert-butyl N-(trans-4-ethynylcyclohexyl)carbamate (1.55 g, 6.93 mmol) synthesized in Reference Example 2, triruthenium dodecacarbonyl (0) (0.0738 g, 0.115 mmol) and 5-(di-tert-butylphosphino)-1',3' ,5'-triphenyl-1'H-[1,4']bipyrazole (0.175 g, 0.346 mmol) were added, and the resultant mixture was stirred under a nitrogen atmosphere at 120°C for 1 hour. After completing the reaction, the solvent was distilled off under reduced pressure, and the thus obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 to 80:20) to obtain a title compound (1.00 g, 2.28 mmol, 49% yield).
    1H-NMR (400MHz, CDCl3) δ: 1.02-1.16 (2H, m), 1.24-1.40 (2H, m), 1.44 (9H, s), 1.62 (3H, s), 1.78-1.88 (1H, m), 1.91-2.00 (2H, m), 2.04-2.12 (2H, m), 2.38 (3H, s), 3.33-3.46 (1H, m), 3.85 (3H, s), 4.37 (1H, br s), 7.53 (1H, s) .
    • (Step 1-2) Methyl (2R)-2-[trans-4-(tert-butoxycarbonylamino)cyclohexyl]-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate
  • From the methyl 2-[trans-4-(tert-butoxycarbonylamino)cyclohexyl]-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate synthesized in step 1-1, each enantiomer was separated under the following conditions:
    • Column: Daicel Corporation, CHIRALCEL OZ-H 4.6 mm ID x 250 mm L
    • Elution Solvent: n-hexane: ethanol = 98:2
    • Flow Rate: 1.00 mL/min
    • Temperature: 25°C
    • First Peak: 10.7 min ([(α]D 20 = -18.3 (C = 0.92, chloroform))
    • Second Peak: 11.7 min ([α]D 20 = +18.3 (C = 0.96, chloroform))
  • In the following steps, the second peak isolated by using a chiral column for separation was used.
    • (Step 1-3) (2R)-2-[trans-4-(tert-Butoxycarbonylamino)cyclohexyl]-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid
  • To the methyl (2R)-2-[trans-4-(tert-butoxycarbonylamino)cyclohexyl]-7-chloro-2,4-dimethyl-1,3-benzodixole-5-carboxylate (the second peak, 0.234 g, 0.532 mmol) separated in step 1-2, tetrahydrofuran (3 mL) and methanol (1.5 mL) were added, and a 1M sodium hydroxide aqueous solution (1.33 mL, 1.33 mmol) was further added to the resultant, followed by stirring at room temperature for 16 hours. After completing the reaction, 1M hydrochloric acid (1.33 mL, 1.33 mmol) was added thereto for neutralization, and dichloromethane was further added thereto for extraction. The thus obtained organic layer was concentrated under reduced pressure to obtain a title compound (0.227 g, 0.532 mmol, 100% yield).
    • (Step 1-4) tert-Butyl N-[trans-4-[(2R)-7-chloro-5-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl]-2,4-dimethyl-1,3-benzodioxol-2-yl] cyclohexyl] carbamate
  • To a dimethylformamide solution (5 mL) of the (2R)-2-[trans-4-(tert-butoxycarbonylamino)cyclohexyl]-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid (0.227 g, 0.532 mmol) synthesized in step 1-3, 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one hydrochloride (0.116 g, 0.586 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.122 g, 0.639 mmol), 1-hydroxy-7-azabenzotriazole (0.0869 g, 0.639 mmol), and N,N-diisopropylethylamine (0.223 mL, 1.28 mmol) were added, and the resultant was stirred under a nitrogen atmosphere at room temperature for 1.5 hours. After completing the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the reaction solution, and the resultant was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The thus obtained residue was dissolved in chloroform, and purified by the silica gel column chromatography (chloroform: methanol = 100:0 to 95:5) to obtain a title compound (0.298 g, 0.532 mmol, 100% yield).
    1H-NMR (400MHz, CDCl3) δ: 1.01-1.16 (2H, m), 1.23-1.38 (2H, m), 1.44 (9H, s), 1.59 (3H, s), 1.76-1.84 (1H, m), 1.88-1.95 (2H, m), 2.02-2.11 (2H, m), 2.22 (3H, s), 2.25 (3H, s), 2.37 (3H, s), 3.30-3.46 (1H, m), 4.35-4.41 (1H, m), 4.49 (2H, d, J = 6.1 Hz), 5.96 (1H, s), 6.87 (1H, s), 7.23 (1H, t, J = 6.1 Hz). MS (APCI) m/z: 560 (M+H)+.
    • (Step 1-5) (2R)-2-(trans-4-Aminocyclohexyl)-7-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide
  • The tert-butyl N-[trans-4-[(2R)-7-chloro-5-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl]-2,4-dimethyl-1,3-benzodioxol-2-yl] cyclohexyl] carbamate (0.298 g, 0.532 mmol) synthesized in step 1-4 was dissolved in methanol (1.3 mL), and a 4M hydrochloric acid-1,4-dioxane solution (1.33 mL, 5.32 mmol) was added thereto followed by stirring at room temperature for 1 hour. After completing the reaction, a saturated sodium bicarbonate aqueous solution was added thereto for neutralization, and 20% methanol-chloroform was used for extraction. The resulting organic layer was washed with a saturated saline solution, dried over sodium sulfate, and then concentrated under reduced pressure to obtain a title compound (0.241 g, 0.524 mmol, 98% yield). MS (APCI) m/z: 460 (M+H)+.
    • (Step 1-6) (2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide
  • The (2R)-2-(trans-4-aminocyclohexyl)-7-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide (17.0 g, 36.9 mmol) synthesized in step 1-5 was dissolved in methanol (200 mL), a 37% formaldehyde aqueous solution (6.29 g, 77.5 mmol) was added thereto, the resultant was stirred at room temperature for 10 minutes, and sodium triacetoxyborohydride (34.2 g, 129 mmol) was added thereto, followed by stirring at room temperature for 16 hours. After completing the reaction, the resultant was neutralized with a 1M sodium hydroxide aqueous solution, and 20% methanol-chloroform was used for extraction. The resulting organic layer was washed with a saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure, and the thus obtained residue was purified by basic silica gel column chromatography (ethyl acetate: methanol = 100:0 to 96:4) to obtain a title compound (15.3 g, 31.4 mmol, 85% yield).
    1H-NMR (400MHz, DMSO-d6) δ: 1.08-1.21 (4H, m), 1.59 (3H, s), 1.77-1.90 (5H, m), 2.03-2.09 (1H, m), 2.11 (6H, s), 2.13 (6H, s), 2.16 (3H, s), 4.21 (2H, d, J = 4.9 Hz), 5.85 (1H, s), 6.84 (1H, s), 8.13 (1H, t, J = 4.9 Hz), 11.48 (1H, s).
    MS (APCI) m/z: 488 (M+H)+.
    • Specific rotation [α]D 20 = +1.0 (C = 1.0, chloroform) Example 2 (2R)-7-Bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide
  • Figure imgb0008
    Figure imgb0009
    • (Step 2-1) Methyl 7-bromo-2-[trans-4-(tert-butoxycarbonylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylate
  • A reaction similar to that of step 1-1 was performed by using the methyl 5-bromo-3,4-dihydroxy-2-methylbenzoate (23.5 g, 90.0 mmol) synthesized in Reference Example 3, the tert-butyl N-(trans-4-ethynylcyclohexyl)carbamate (22.1 g, 99.0 mmol) synthesized in Reference Example 2, triruthenium dodecacarbonyl (0) (1.44 g, 2.25 mmol) and 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-[1,4']bipyrazole (3.42 g, 6.75 mmol) to obtain a title compound (38.9 g, 80.3 mmol, 89% yield).
    1H-NMR (400MHz, CDCl3) δ: 1.04-1.15 (2H, m), 1.25-1.38 (2H, m), 1.44 (9H, s), 1.63 (3H, s), 1.79-1.87 (1H, m), 1.91-1.99 (2H, m), 2.04-2.12 (2H, m), 2.38 (3H, s), 3.31-3.46 (1H, m), 3.84 (3H, s), 4.37 (1H, br s), 7.67 (1H, s) .
    • (Step 2-2) (2R)-Methyl 7-bromo-2-[trans-4-(tert-butoxycarbonylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylate
  • From the methyl 7-bromo-2-[trans-4-(tert-butoxycarbonylamino)cyclohexyl] -2,4-dimethyl-1,3-benzodioxole-5-carboxylate synthesized in step 2-1, each enantiomer was separated under the following conditions:
    • Column: Daicel Corporation, CHIRALCEL OZ-H 4.6 mm ID x 250 mm L
    • Elution Solvent: n-hexane: ethanol = 98:2
    • Flow Rate: 1.00 mL/min
    • Temperature: 25°C
    • First Peak: 11.2 min (specific rotation [α]D 20 = -6.5 (C = 1.0, chloroform))
    • Second Peak: 12.3 min (specific rotation [α]D 20 = +6.3 (C = 1.0, chloroform))
  • In the following steps, the second peak isolated by using a chiral column for separation was used.
    • (Step 2-3) (2R)-7-Bromo-2-[trans-4-(tert-butoxycarbonylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid
  • A reaction similar to that of step 1-3 was performed by using the (2R)-methyl 7-bromo-2-[trans-4-(tert-butoxycarbonylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylate (the second peak, 0.956 g, 1.97 mmol) separated in step 2-2, tetrahydrofuran (6 mL), methanol (3 mL), and a 1M sodium hydroxide aqueous solution (2.96 mL, 2.96 mmol) to obtain a title compound (0.903 g, 1.92 mmol, 97% yield).
    • (Step 2-4) tert-Butyl N-[trans-4-[(2R)-7-bromo-5-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl]-2,4-dimethyl-1,3-benzodioxol-2-yl] cyclohexyl] carbamate
  • A reaction similar to that of step 1-4 was performed by using the (2R)-7-bromo-[trans-4-(tert-butoxycarbonylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid (0.903 g, 1.92 mmol) synthesized in step 2-3, dimethylformamide (20 mL), 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one hydrochloride (0.399 g, 2.11 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.442 g, 2.30 mmol), 1-hydroxy-7-azabenzotriazole (0.314 g, 2.30 mmol), and N,N-diisopropylethylamine (0.803 mL, 4.61 mmol) to obtain a title compound (0.801 g, 1.32 mmol, 69% yield).
    1H-NMR (400MHz, CDCl3) δ: 1.03-1.15 (2H, m), 1.21-1.38 (2H, m), 1.44 (9H, s), 1.59 (3H, s), 1.75-1.84 (1H, m), 1.89-1.97 (2H, m), 2.02-2.10 (2H, m), 2.21 (3H, s), 2.26 (3H, s), 2.37 (3H, s), 3.34-3.45 (1H, m), 4.41-4.45 (1H, m), 4.49 (2H, d, J = 6.0 Hz), 5.95 (1H, s), 7.00 (1H, s), 7.18 (1H, t, J = 6.0 Hz). MS (APCI) m/z: 604, 606 (M+H)+.
    • (Step 2-5) (2R)-2-(trans-4-Aminocyclohexyl)-7-bromo-N-[ (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide
  • A reaction similar to that of step 1-5 was performed by using the tert-butyl N-[trans-4-[(2R)-7-boromo-5-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl]-2,4-dimethyl-1,3-benzodioxol-2-yl]cyclohexyl]carbamate (0.801, g, 1.32 mmol) synthesized in step 2-4, methanol (1.5 mL), and a 4M hydrochloric acid-1,4-dioxane solution (1.67 mL, 6.62 mmol) to obtain a title compound (0.668 g, 1.32 mmol, 100% yield).
    1H-NMR (400MHz, DMSO-d6) δ: 0.93-1.05 (2H, m), 1.08-1.23 (2H, m), 1.59 (3H, s), 1.73-1.85 (5H, m), 2.10 (3H, s), 2.11 (3H, s), 2.16 (3H, s), 2.39-2.49 (1H, m), 4.21 (2H, d, J = 4.9 Hz), 5.85 (1H, s), 6.94 (1H, s), 8.14 (1H, t, J = 4.9 Hz).
    MS (ESI) m/z: 504, 506 (M+H)+.
    • (Step 2-6) (2R)-7-Bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide
  • A reaction similar to that of step 1-6 was performed by using the (2R)-2-(trans-4-aminocyclohexyl)-7-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide (21.1 g, 41.7 mmol) synthesized in step 2-5, methanol (250 mL), a 37% formaldehyde aqueous solution (7.12 g, 87.8 mmol), and sodium triacetoxyborohydride (38.8 g, 146 mmol) to obtain a title compound (15.1 g, 28.4 mmol, 68% yield).
    1H-NMR (400MHz, DMSO-d6) δ: 1.08-1.20 (4H, m), 1.59 (3H, s), 1.75-1.90 (5H, m), 2.02-2.12 (1H, m), 2.09 (3H, s), 2.11 (3H, s), 2.13 (6H, s), 2.16 (3H, s), 4.21 (2H, d, J = 4.9 Hz), 5.85 (1H, s), 6.93 (1H, s), 8.12 (1H, t, J = 4.9 Hz), 11.47 (1H, s).
    MS (APCI) m/z: 532, 534 (M+H)+.
    • Specific rotation [α]D 20 = -7.2 (C = 1.0, chloroform) Example 3 7-Bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide
  • Figure imgb0010
    • (Step 3-1) 7-Bromo-2-[trans-4-(tert-butoxycarbonylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodixole-5-carboxylic acid
  • A reaction similar to that of step 1-3 was performed by using the methyl 7-bromo-2-[trans-4-(tert-botoxycarbonylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylate (23.5 g, 48.5 mmol) synthesized in step 2-1, tetrahydrofuran (120 mL), methanol (60 mL), and a 1M sodium hydroxide aqueous solution (72.8 mL, 72.8 mmol) to obtain a title compound (22.8 g, 48.5 mmol, 100% yield).
    1H-NMR (CDCl3) δ: 1.04-1.16 (2H, m), 1.25-1.38 (2H, m), 1.44 (9H, s), 1.64 (3H, s), 1.80-1.90 (1H, m), 1.92-2.00 (2H, m), 2.06-2.16 (2H, m), 2.41 (3H, s), 3.35-3.48 (1H, m), 4.40 (1H, br s), 7.80 (1H, s).
    MS (ESI) m/z: 468, 470 (M-H)-.
    • (Step 3-2) tert-Butyl N-[trans-4-[(7-bromo-5-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methylcarbamoyl]-2,4-dimethyl-1,3-benzodioxol-2-yl]cyclohexyl]carbamate
  • A reaction similar to that of step 1-4 was performed by using the 7-bromo-2-[trans-4-(tert-butoxycarbonylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid (22.8 g, 48.5 mmol) synthesized in step 3-2, dimethylformamide (300 mL), 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one hydrochloride (10.1 g, 53.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.2 g, 58.2 mmol), 1-hydroxy-7-azabenzotriazole (7.92 g, 58.2 mmol), and N,N-diisopropylethylamine (20.3 mL, 146 mmol) to obtain a title compound (26.8 g, 44.3 mmol, 91% yield).
    1H-NMR (400MHz, CDCl3) δ: 1.02-1.15(2H, m), 1.23-1.40 (2H, m), 1.43 (9H, s), 1.59 (3H, s), 1.75-1.84 (1H, m), 1.89-1.97 (2H, m), 2.02-2.10 (2H, m), 2.21 (3H, s), 2.26 (3H, s), 2.37 (3H, s), 3.34-3.45 (1H, m), 4.39 (1H, d, J = 8.4 Hz), 4.49 (2H, d, J = 5.5 Hz), 5.96 (1H, s), 7.00 (1H, s), 7.21 (1H, t, J = 5.5 Hz).
    MS (ESI) m/z: 604, 606 (M+H)+.
    • (Step 3-3) (2R)-2-(trans-4-Aminocyclohexyl)-7-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide
  • A reaction similar to that of step 1-5 was performed by using the tert-butyl N-[trans-4-[7-bromo-5-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl]-2,4-dimethyl-1,3-benzodioxol-2-yl] cyclohexyl] carbamate (6.04 g, 9.99 mmol) synthesized in step 3-2, methanol (10 mL), and a 4M hydrochloric acid-1,4-dioxane solution (12.5 mL, 50.0 mmol) to obtain a title compound (4.20 g, 8.30 mmol, 83% yield).
    1H-NMR (400MHz, DMSO-d6) δ: 0.93-1.05 (2H, m), 1.08-1.23 (2H, m), 1.59 (3H, s), 1.73-1.85 (5H, m), 2.10 (3H, s), 2.11 (3H, s), 2.16 (3H, s), 2.39-2.49 (1H, m), 4.21 (2H, d, J = 4.9 Hz), 5.85 (1H, s), 6.94 (1H, s), 8.14 (1H, t, J = 4.9 Hz).
    MS (ESI) m/z: 504, 506 (M+H)+.
    • (Step 3-4) 7-Bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide
  • A reaction similar to that of step 1-6 was performed by using the 2-(trans-4-aminocyclohexyl)-7-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide (21.0 g, 41.6 mmol) synthesized in step 3-3, dichloromethane (500 mL), a 37% formaldehyde aqueous solution (8.45 g, 104 mmol), and sodium triacetoxyborohydride (55.2 g, 208 mmol) to obtain a title compound (20.0 g, 37.6 mmol, 90% yield).
    1H-NMR (400MHz, DMSO-d6) δ: 1.08-1.23 (4H, m), 1.59 (3H, s), 1.75-1.90 (5H, m), 2.02-2.09 (1H, m), 2.10 (3H, s), 2.11 (3H, s), 2.13 (6H, s), 2.16 (3H, s), 4.21 (2H, d, J = 4.9 Hz), 5.85 (1H, s), 6.94 (1H, s), 8.14 (1H, t, J = 4.9 Hz), 11.48 (1H, s).
    MS (APCI) m/z: 532, 534 (M+H)+.
    • Example 4 (2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide p-toluenesulfonate
  • To the (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide (0.202 g, 0.414 mmol) synthesized in Example 1, acetone (7.97 mL) and a 4.00 mol/L p-toluenesulfonic acid aqueous solution (0.103 mL, 0.414 mmol) were added at room temperature. Thereafter, the resulting solution was stirred at 40°C for about 20 hours, followed by stirring at room temperature for about 0.5 hours, and then the precipitated solid was filtered off. Subsequently, the solid was dried overnight at room temperature to obtain a title compound (0.256 g, 99% yield).
    1H-NMR (DMSO-d6) δ: 1.15-1.32 (2H, m), 1.36-1.50 (2H, m), 1.62 (3H, s), 1.88-2.06 (5H, m), 2.11 (3H, s), 2.12 (3H, s), 2.17 (3H, s), 2.29 (3H, s), 2.70 (3H, s), 2.71 (3H, s), 3.10-3.22 (1H, m), 4.22 (2H, d, J = 5.0 Hz), 5.86 (1H, s), 6.87 (1H, s), 7.11 (2H, d, J = 8.2 Hz), 7.48 (2H, d, J = 8.2 Hz), 8.14 (1H, t, J = 5.0 Hz), 9.31 (1H, br s), 11.48 (1H, s).
    Elemental analysis Anal. Calcd for C26H34ClN3O4·C7H8O3S: C, 60.03; H, 6.41; N, 6.36; Cl, 5.37; S, 4.86. Found: C, 58.81; H, 6.48; N, 6.21; Cl, 5.32; S, 4.85.
    • Test Example 1 Growth Inhibition Effect against TL-Om1
  • A cell line TL-Om1 derived from an ATL patient tumor cell was provided by Dr. Kazuo Sugamura, Chief Executive, Local Incorporated Administrative Agency Miyagi Prefectural Hospital Organization. The cell line TL-Om1 was suspended in a medium (RPMI 1640 medium (Invitrogen) supplemented with 10% fetal bovine serum (FBS, Invitrogen)), and seeded in a 12-well plate at a density of 1 x 105 cells/1 mL/well. Immediately after the seeding, a dilution series of the compound of Example 1 or Example 3 prepared by using DMSO was added thereto, and the resultant was cultured under conditions of 37°C and 5% CO2. The cells were collected every two or three days, and passage-cultured by transferring 300 µL of the culture medium to a 12-well plate containing 1 mL of a fresh medium. Besides, the dilution series of the compound of Example 1 or Example 3 was added again to continuously carry out the cultivation. On days 3, 5, 7, 10, 12 and 14 after starting the cultivation, the cells were collected from the culture medium to obtain a cell density, and thus, the influence of the compound of Example 1 or Example 3 on the cell growth was examined. The number of cells on each of these days was obtained by WST-8 (Dojindo Laboratories). The cultured cells were seeded in a 96-well plate by 100 µL, WST-8 was added to each well to a final concentration of 10%, and the resultant plate was incubated at 37°C for 2 hours. An absorbance at 450 nm of each sample was measured by using a plate reader (iMark Microplate Reader, Biorad). A calibration curve between the number of cells and the absorbance was obtained, and the number of cells was calculated on the basis of the absorbance obtained in an actual test. The number of cells was calculated in each passage, and the cell growth rate of each compound-treated group was calculated assuming that the cell growth of a DMSO-treated group was 100%. The results are illustrated in Figures 1 and 2.
    • Test Example 2 Growth Inhibition Effect in ATL Patient-derived Sample
  • As ATL patient-derived peripheral blood, samples diagnosed as ATL in accordance with criteria of WHO classification and Shimoyama classification (Yamaguchi K., Watanabe T. (2002)) in facilities registered in Joint Study on Predisposing Factors of ATL Development (JSPFAD) were used. From the whole blood of ATL patients of 26 cases (including 19 cases for the compound of Example 1; and 7 cases for the compound of Example 3), peripheral blood monocular cells (PBMCs) containing tumor cells were obtained by centrifugation using Ficoll (GE Healthcare). The PBMCs were suspended in a medium (PRMI 1640 medium supplemented with 10% patient plasma), and seeded in a 48-well plate at a density of 3 x 105 cells/300 µL/well (ATL Nos. 1 to 5) or 2 x 105 cells/300 µL/well (ATL Nos. 6 to 26). Besides, in order to retain long-term cultivation of ATL cells expressing IL-2R (CD25), IL-2 (R & C Systems, Inc.) was added thereto to a final concentration of 10 ng/mL. After seeding the cells, a dilution series of each compound prepared by using DMSO was added thereto, and the resultant was cultured under conditions of 37°C and 5% CO2 for 7 days. The thus cultured cells were seeded in a 96-well plate by 100 µL, WST-8 was added to each well to a final concentration of 10%, the resulting plate was incubated at 37°C for 4 hours, and an absorbance at 450 nm was measured as an index of the cell density in the medium solution. The results are illustrated in Figure 3. As a result, it was revealed that the compound can be used for treating ATL.
    • Test Example 3 PVL Reduction Effect in Carrier-derived Sample
  • From whole blood of 9 cases diagnosed as an HTLV-1 carrier by an antibody test in facilities registered in JSPFAD, PBMCs containing HTLV-1 infected cells were obtained by centrifugation using Ficoll. The PBMCs were suspended in a medium (RPMI 1640 medium supplemented with 10% FBS), and seeded in a 48-well plate at a density of 5 x 105 cells/250 µL/well. Thereafter, DMSO or the compound of Example 1 or Example 3 in a final concentration of 100 nM was added thereto, and the resultant was cultured under conditions of 37°C and 5% CO2 for 10 to 12 days. The cultured cells were collected, and genomic DNA was extracted therefrom by using QIAmp DNA Blood Mini Kit (QIAGEN). As a ratio of infected cells in a cell population thus cultured, copy number of HTLV-1 was measured by using a real time PCR system (7500 Real Time PCR System, Applied Biosystems, Inc.). As an internal control, the number of RNase P genes was simultaneously measured to calculate the ratio of infected cells (PVL). Primers and a probe used in the real time PCR had the following sequences:
  • [Formula 9]
    • Forward primer pX2-S
      5'-CGGATACCCAGTCTACGTGTT-3'
    • Reverse primer pX2-AS
      5'-CAGTAGGGCGTGACGATGTA-3'
    • FAM-labeled pX2 probe
      5'-CTGTGTACAAGGCGACTGGTGCC-3'
  • A primer and a probe for the RNase P genes were purchased from Applied Biosystems, Inc.
  • Assuming that the PVL of the DMSO-treated group was 100%, relative PVL change was calculated and illustrated in Figure 4. In groups treated with the present compound, PVL was remarkably lowered as compared with that of the DMSO-treated group. As a result, it was revealed that the compound lowers the incidence rate of ATL in an HTLV-1 carrier.
  • It was revealed, as a result of Test Example 1, that an EZH1/2 inhibiting compound dose-dependently and significantly reduced the cell growth of TL-Om1 cells. Besides, the compound significantly reduced cell survival of ATL patient-derived tumor cells. Furthermore, it was confirmed that the ratio of HTLV-1 infected cells present in the carrier peripheral blood was remarkably reduced. This suggests that the compound induces cell death of the HTLV-1 infected cells.
    • SEQUENCE LISTING
    • <110> Daiichi Sankyo Company, Limited
      The University of Tokyo
    • <120> Agent for treating and/or preventing Adult T cell leukemia/lymphoma
    • <130> PD20-9015WO
    • <150> JP 2015-151170
      <151> 2015-07-30
    • <160> 3
    • <170> PatentIn version 3.5
    • <210> 1
      <211> 21
      <212> DNA
      <213> Artificial Sequence
    • <220>
      <223> forward primer pX2-S
    • <400> 1
      cggataccca gtctacgtgt t   21
    • <210> 2
      <211> 20
      <212> DNA
      <213> Artificial Sequence
    • <220>
      <223> reverse primer pX2-AS
    • <400> 2
      cagtagggcg tgacgatgta   20
    • <210> 3
      <211> 23
      <212> DNA
      <213> Artificial Sequence
    • <220>
      <223> FAM-labeled pX2 probe
    • <400> 3
      ctgtgtacaa ggcgactggt gcc   23

Claims (8)

  1. 7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, or 7-bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, for use in treating adult T cell leukemia/lymphoma in a patient suffering from adult T cell leukemia/lymphoma.
  2. (2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, for use in treating adult T cell leukemia/lymphoma in a patient suffering from adult T cell leukemia/lymphoma.
  3. (2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide p-toluenesulfonate, for use in treating adult T cell leukemia/lymphoma in a patient suffering from adult T cell leukemia/lymphoma.
  4. (2R)-7-Bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, for use in treating adult T cell leukemia/lymphoma in a patient suffering from adult T cell leukemia/lymphoma.
  5. 7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, or 7-bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, for use in preventing onset of adult T cell leukemia/lymphoma in a subject of a human adult T cell leukemia virus type I (HTLV-1) carrier.
  6. (2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, for use in preventing onset of adult T cell leukemia/lymphoma in a subject of a human adult T cell leukemia virus type I (HTLV-1) carrier.
  7. (2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide p-toluenesulfonate, for use in preventing onset of adult T cell leukemia/lymphoma in a subject of a human adult T cell leukemia virus type I (HTLV-1) carrier.
  8. (2R)-7-Bromo-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide or a pharmaceutically acceptable salt thereof, for use in preventing onset of adult T cell leukemia/lymphoma in a subject of a human adult T cell leukemia virus type I (HTLV-1) carrier.
EP16830602.5A 2015-07-30 2016-07-29 Therapeutic and/or prophylactic agent for adult t cell leukemia/lymphoma Active EP3329917B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2015151170 2015-07-30
PCT/JP2016/072262 WO2017018499A1 (en) 2015-07-30 2016-07-29 Therapeutic and/or prophylactic agent for adult t cell leukemia/lymphoma

Publications (3)

Publication Number Publication Date
EP3329917A1 EP3329917A1 (en) 2018-06-06
EP3329917A4 EP3329917A4 (en) 2019-03-13
EP3329917B1 true EP3329917B1 (en) 2020-09-02

Family

ID=57885177

Family Applications (1)

Application Number Title Priority Date Filing Date
EP16830602.5A Active EP3329917B1 (en) 2015-07-30 2016-07-29 Therapeutic and/or prophylactic agent for adult t cell leukemia/lymphoma

Country Status (11)

Country Link
US (1) US10434091B2 (en)
EP (1) EP3329917B1 (en)
KR (1) KR102578297B1 (en)
CN (1) CN107847497B (en)
AU (1) AU2016299614B2 (en)
BR (1) BR112018001688B1 (en)
CA (1) CA2993605C (en)
ES (1) ES2828961T3 (en)
HK (1) HK1253319A1 (en)
TW (1) TWI711451B (en)
WO (1) WO2017018499A1 (en)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7125353B2 (en) 2017-01-19 2022-08-24 第一三共株式会社 Pharmaceutical composition for use in treating HTLV-1-associated myelopathy
BR112020021194A2 (en) 2018-04-18 2021-03-23 Constallation Pharmaceuticals, Inc. modulators of methyl modifying enzymes, compositions and uses thereof
EP3797108B1 (en) 2018-05-21 2022-07-20 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
TWI837231B (en) * 2018-11-29 2024-04-01 日商第一三共股份有限公司 Pharmaceutical combination containing ezh1/2 dual inhibitor and use thereof
CN118236503A (en) * 2019-07-24 2024-06-25 星座制药公司 EZH2 inhibition combination therapy for the treatment of cancer
EP4011452A4 (en) * 2019-08-08 2023-07-26 Daiichi Sankyo Company, Limited ANTI-CCR4 ANTIBODY RESISTANT CANCER THERAPEUTIC AGENT
US20220298222A1 (en) 2019-08-22 2022-09-22 Juno Therapeutics, Inc. Combination therapy of a t cell therapy and an enhancer of zeste homolog 2 (ezh2) inhibitor and related methods
EP4180426A4 (en) * 2020-07-08 2024-08-07 Daiichi Sankyo Company, Limited PROCESS FOR THE PRODUCTION OF 1,3-BENZODIOXOLE DERIVATIVE
CN116496263A (en) * 2022-01-27 2023-07-28 江苏天士力帝益药业有限公司 EZH1/2 inhibitor and its preparation and application in anti-tumor treatment
CN115974856B (en) * 2022-12-28 2023-08-11 北京康立生医药技术开发有限公司 Preparation method of drug valmotustat for treating adult T-cell leukemia lymphoma

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003244000A1 (en) * 2002-06-26 2004-01-19 Signal Creation Inc. DRUG COMPOSITION CONTAINING NF-KappaB INHIBITOR
WO2009006577A2 (en) 2007-07-03 2009-01-08 The Regents Of The University Of Michigan Compositions and methods for inhibiting ezh2
WO2010051085A1 (en) * 2008-10-30 2010-05-06 Oncotherapy Science, Inc. 7-hydroxy-benzoimidazole-4-yl-methanone derivatives and pbk inhibitors containing the same
KR102302830B1 (en) * 2014-03-17 2021-09-15 다이이찌 산쿄 가부시키가이샤 1,3-benzodioxole derivative

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Also Published As

Publication number Publication date
TW201713335A (en) 2017-04-16
KR20180032596A (en) 2018-03-30
WO2017018499A1 (en) 2017-02-02
CN107847497A (en) 2018-03-27
EP3329917A4 (en) 2019-03-13
US20180200238A1 (en) 2018-07-19
BR112018001688A2 (en) 2018-09-18
TWI711451B (en) 2020-12-01
BR112018001688B1 (en) 2023-05-02
EP3329917A1 (en) 2018-06-06
AU2016299614B2 (en) 2020-05-07
CA2993605A1 (en) 2017-02-02
CA2993605C (en) 2020-01-07
US10434091B2 (en) 2019-10-08
AU2016299614A1 (en) 2018-02-08
HK1253319A1 (en) 2019-06-14
KR102578297B1 (en) 2023-09-13
CN107847497B (en) 2021-03-30
ES2828961T3 (en) 2021-05-28

Similar Documents

Publication Publication Date Title
EP3329917B1 (en) Therapeutic and/or prophylactic agent for adult t cell leukemia/lymphoma
US20230065463A1 (en) Compounds and uses thereof
SA516370523B1 (en) Therapeutically active compounds and their methods of use
JP2021515010A (en) Compounds with ferrotosis-inducing activity and how to use them
TW202140485A (en) Compounds and uses thereof
WO2018135556A1 (en) Pharmaceutical composition used for treatment of htlv-1-associated myelopathy
US10329626B2 (en) NOL3 is a predictor of patient outcome
US20230012172A1 (en) Compositions and methods for treatment of platinum-based chemotherapeutic resistant tumors
JP6009135B1 (en) Treatment and / or prevention agent for adult T-cell leukemia lymphoma
EP2187889B1 (en) Use of purine derivatives for the manufacture of a medicament
CA3148858A1 (en) Therapeutic agent for cancer having resistance to anti-ccr4 antibody
Guo et al. Remodeling the immune microenvironment for gastric cancer therapy through antagonism of prostaglandin E2 receptor 4
EP4188447A1 (en) Compounds and uses thereof
US20090075972A1 (en) Use of Midostaurin for Treating Gastrointestinal Stromal Tumors
US20240140947A1 (en) Compound for the treatment of cancer
CN107840847A (en) Deuterated 3 (4,5 substituted-amino pyrimidine) phenyl derivatives and its application
EA047751B1 (en) COMPOUNDS AND METHODS OF THEIR APPLICATION
CN118344339A (en) Small molecule compounds targeting BCL 9/beta-catenin interactions

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20180105

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20190213

RIC1 Information provided on ipc code assigned before grant

Ipc: C07D 405/12 20060101ALI20190207BHEP

Ipc: A61P 35/02 20060101ALI20190207BHEP

Ipc: A61K 31/443 20060101AFI20190207BHEP

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1253319

Country of ref document: HK

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20200415

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1307997

Country of ref document: AT

Kind code of ref document: T

Effective date: 20200915

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602016043416

Country of ref document: DE

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201202

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201202

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20201203

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20200902

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 1307997

Country of ref document: AT

Kind code of ref document: T

Effective date: 20200902

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210104

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2828961

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20210528

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210102

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602016043416

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20210603

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20210731

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210731

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210731

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210729

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210729

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210731

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20160729

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230502

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200923

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20230801

Year of fee payment: 8

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20240606

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20240611

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200902

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20240612

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20240604

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20240801

Year of fee payment: 9